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AN UNBIASED MONTHLY COVERING ALL THINGS PSYCHIATRIC
VOLUME 5, NUMBER 1
SSRI Nonresponse: What to Do Next?
By Shalom Feinberg, M.D. ost psychiatrists would agree that the first step in treating depression is to start one of the SSRIs, because they are effective, safe, have a broad spectrum of both anti-anxiety and antidepressant activity, and are often cheap, since all SSRIs but Lexapro are now available generically. How cheap is cheap? At Walmart pharmacies, you can now purchase fluoxetine for about 13 cents a pill, or only $4 per month for the original “miracle” antidepressant. However, we know that many patients will not respond or will not tolerate an SSRI, and the Star-D study was supposed
to provide guidance on what to do next. But, as you have read elsewhere in this issue, STAR-D’s results fell short of these expectations. Underlining the inadequacy of the existing database on this issue, a just published systematic review of all available research on antidepressant switching options for SSRI nonresponders concluded there are no distinct recommendations on how to next treat these patients (Ruhe et al, J Clin Psychiatry 2006;67:1836-1855). We’re left with our clinical experiences and preferences, along with a smattering of relevant research that has been published over the years.
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IN THIS ISSUE:
Focus of the Month:
Antidepressant Round-up 2007
• SSRI Nonresponse: What to Do Next? • STAR-D Results: How do the results help our Depressed Patients? • Research Updates • Expert Q & A: Michael Thase M.D. on Deciphering Antidepressant Research
Dr. Feinberg has disclosed that he has no significant relationships with or financial interests in any commercial companies pertaining to this educational activity.
How do STAR-D Results Help our Depressed Patients?
The following imaginary case vignette helps us examine the clinical relevance of the major findings of the STAR-D trial. The patient was a 46-year old female epidemiologist, who was referred to me by her primary care physician for symptoms of moderate depression. Pt.: I had asked my doctor about the new findings from the NIMH depression study. He said it was complicated, and suggested that I bring my questions to you. Dr. Carlat: You’re probably talking about the STAR-D trial? Pt.: That’s the one. It’s billed in NIMH press releases as “the nation’s largest clinical trial for depression.” I’ve heard that most of the results are out, and I was hoping that you could help me understand them. What’s the best treatment for me, according to the study? Dr. Carlat: Let’s start at the beginning. This was a $35 million study, funded entirely by taxpayers, with no drug industry money. In the first step of the trial, 2876 patients were started on Celexa, and after about 7 weeks of treatment on an average dose of 41.7 mg/day, 790 of those patients, or 28%, got well (Trivedi et al, Am J Psychiatry 2006;163:28-40). Pt.: You mean I only have a 28% chance of improving after almost 2 months on an antidepressant? That doesn’t sound very good. Dr. Carlat: Not so fast. Unlike most antidepressant studies in the past, this one focused on remission, meaning the virtual absence of any depressive symptom. Most other studies have been content to look at response, defined as a 50% reduction in symptoms. Pt.: All right, but I’ve been so miserable lately that a 50% improvement sounds just fine to me. What were the response rates in that study? Dr. Carlat: In the Celexa arm, the response rate was 47%. Pt.: That sounds better, but still not great. Is this the best response rate psychiatrists have to offer – less than 50%? Dr. Carlat: That depends on the drug, the population, and the design of the study. The STAR-D study was an open-label study, meaning that there was no placebo control and all patients knew what pill they were taking. These kinds of studies typically yield very high response rates, in the range of 60%-70%. But the STAR-D study enrolled patients who are more severely ill than in most studies. The typical STAR-D patient had continuous depressive symptoms for at least 2 years, and six prior episodes of depression. Pt.: So do these results apply to me? This
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Learning objectives for this issue: 1. Describe rational strategies in approaching SSRI nonresponse. 2. Outline the limitations of the STAR-D study. 3. Describe the results of studies comparing venlafaxine with SSRIs. This CME activity is intended for psychiatrists, psychiatric nurses, and other health-care professionals with an interest in the diagnosis and treatment of psychiatric disorders.
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SSRI Nonresponse: What to do Next?
Here are TCPR’s guidelines for how to deal with SSRI non-response: patients who tell us they have improved when we have increased their doses, no matter what the studies say. A reasonable approach, then, is to escalate the SSRI dose by about half the “unit dose” (e.g., the unit dose of fluoxetine is 20 mg, of sertraline 50 mg, etc.) if there is incomplete response after 2 to 4 weeks, and to keep escalating until you achieve either: A) A satisfactory response; or B) Intolerable side effects. Switch or Augment? This was the major disappointment of STAR-D, namely, that it provided no guidance on when to make this crucial decision. So we fall back on clinical lore, which offers the following: Switch meds for patients who: • Have had no response whatsoever; • Are unable to tolerate a given SSRI, or • Prefer a simpler (and cheaper) single drug regimen rather then taking two agents. Augment for patients who: • Have only a partial response • Have failed a number of individual drug switches, or, • Have more severe depressive illness. In this article we don’t have room to delve into the vast world of augmentation strategies, but we recommend an excellent recent article by Debattista for those who are interested (Debattista, J Psychopharmacology 2006;20, No. 3 suppl: 11-18). Switch to What? Is it worthwhile to switch to a different SSRI or should we go into a different class immediately? It is clear that in both the STAR-D trial and in other studies, some patients intolerant to an initial SSRI trial may in fact tolerate and respond to a second SSRI (see review by Ruhe et al referred to above). Other studies have shown that patients who tolerate but do not respond to the first SSRI will often respond to second. For instance, in one of the better performed SSRI switch studies, 57 acutely depressed patients with at least 6 weeks of nonresponse to Prozac (fluoxeContinued from Page 1
Patience is a virtue for some patients, but counterproductive for others. One useful clinical nugget from Star-D is the reminder that chronically ill or recurrently depressed patients may take many weeks to get well. Patients on Celexa (citalopram) in Step One of STAR-D required an average of 5.7 weeks to respond, and 6.7 weeks to fully remit, despite a fairly aggressive dosing titration schedule leading to an average dose of 41.7 mg/day (Trivedi et al, Am J Psychiatry 2006;163:28-40). On the other hand, recent studies have shown that up to 60% of acutely depressed patients will show onset of a response to an antidepressant within the first two weeks, which challenges the clinical lore that antidepressants take four weeks to kick in (see, for example, the recent review in Katz et al, J Clin Psychopharmacology 2006;26:549-553). Thus, if you are treating a patient who is fairly new to psychiatric treatment, and there is absolutely no response within two weeks on a therapeutic dose, chances are low that they will ever respond to that agent, and you should seriously consider changing strategies. The STAR-D patients probably fit into a very different category, since they were chronically depressed, with an average continuous period of depression of two years prior to study entry.
Bump up the dose? Maybe. Just about every review article you will read on treatment resistant depression will suggest “dose optimization,” meaning that you should increase the dose until there is either a response or limiting side effects. However, the actual data in support of this practice is meager. For example, a recent systematic review of eight controlled trials that involved dose escalation of SSRIs found no value in increasing the SSRI dose within the first four weeks. After eight weeks, increasing the dose yielded some limited benefit, but only in patients who had already shown at least a partial response (Ruhe et al, Br J Psychiatry, 2006;189:309-316.) So where does this leave us? The fact is that we all have experience with
tine, avg. length of nonresponse, 5.9 months, avg. dose, 31 mg/day) were immediately switched to Celexa (citalopram, up to 60 mg/day, avg., 39 mg/day). In this trial, 63% of patients responded to Celexa over 12 weeks (Thase, J Clin Psychiatry 2001;62: 683-687). But this study, like all other switch studies in the literature, was neither controlled nor double-blind. Because of this, we have no way of knowing for sure whether switching to a different SSRI is any more effective than simply staying the course on the original medication. Switching out of class. When switching out of class, most psychiatrists choose one of the SNRIs (serotonin norepinephrine reuptake inhibitors), either Effexor XR (venlafaxine XR) or Cymbalta (duloxetine). There is more data supporting the efficacy of switching to Effexor (see, for example, Poirier et al, Br J Psychiatry 1999;175: 12-16 and Baldomero et al, Depression Anxiety 2005; 22:68-76) but this data may simply reflect the fact that Effexor’s been around longer than Cymbalta. Cymbalta has some advantages over Effexor, including an easier titration schedule and a lower rate of severe discontinuation symptoms (Perahia et al, J Affective Dis 2005;89:207-212). While we would all like to believe that switching to Wellbutrin works well (because of its lack of sexual side effects), there’s not much data to support its efficacy in treatment-resistant depression. In STAR-D, the Wellbutrin switch did as well as Effexor XR and Zoloft, but the lack of blinding or placebo makes all of STAR-D’s results questionable. Switching to Remeron (mirtazepine) is also an option, although its side effects of weight gain and sedation make it unappealing to many. If the SNRI switch is ineffective, we recommend going to one of the “bigger guns” – either a tricyclic (TCA) or a monoamine oxidase inhibitor (MAOI). Of course, these switches can be tricky because of drug interactions. Prozac and Paxil can increase serum levels of tricyclics; all SSRIs interact with MAOIs,
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The Carlat Psychiatry Report
Publisher and Editor-in-chief: Daniel J. Carlat, M.D., is Assistant Clinical Professor of Psychiatry at Tufts University School of Medicine and maintains a private practice in Newburyport, Massachusetts. He graduated from the psychiatric residency at Massachusetts General Hospital in 1995, and is founding editor of The Practical Guide Series in Psychiatry, published by Lippincott Williams & Wilkins. Associate Editor: Marcia L. Zuckerman, M.D., practices psychiatry at HRI/Arbour in Brookline, Massachusetts. Editorial Board: Dan Egli, Ph.D., Private Practice, Williamsport, PA. Ivan Goldberg, M.D., Creator, Depression Central website, psychopharmacologist in private practice, New York City. Alan D. Lyman, M.D., Child and adolescent psychiatrist in private practice, New York City. Robert L. Mick, M.D., Medical Director of DePaul Addiction Services, Rochester, New York. Michael Posternak, M.D., Assistant Clinical Professor of Psychiatry, Brown University School of Medicine. Dr. Carlat, with editorial assistance from Dr. Zuckerman, is the author (unless other authorship is specified) of all articles and interviews for The Carlat Psychiatry Report. All editorial content is peer reviewed by the editorial board. Dr. Carlat, Dr. Goldberg, Dr. Lyman, Dr. Mick, Dr. Posternak and Dr. Zuckerman have disclosed that they have no significant relationships with or financial interests in any commercial companies pertaining to this educational activity.
How do STAR-D Results Help our Depressed Patients?
is the first bout I’ve had with depression. Dr. Carlat: Remission rates were highest in patients like you – that is, well-educated females who didn’t have medical problems or other psychiatric problems. Pt.: What if you start me on Celexa and I don’t improve? What should we do then, according to STAR-D? Dr. Carlat: One of the main goals of STAR-D was to answer that very question. Patients who failed the initial Celexa trial were assigned to different treatment strategies, including switching from Celexa to a different antidepressant, augmenting the Celexa with a second drug, or receiving cognitive behavioral therapy. Pt.: Sounds like a good study. Now psychiatrists will know which treatment strategy is the best one to turn to when patients fail their first medication. Dr. Carlat: Unfortunately, the study didn’t end up providing any answers to that question. The reason is that patients were not randomly assigned to different treatments. Instead, they were allowed to choose which type of treatment they wanted to receive. Because of this, we can’t really compare results in the different treatment arms. Pt.: That doesn’t sound like a very smart way to do research. Why didn’t they randomize? Dr. Carlat: Mainly because they were afraid that too many patients would drop out of the study if they were forced to be randomly assigned. And if too many people drop out of a study, you have a couple of major problems. First, whatever patients are left in the study may not be very representative of the the patients we see in our practices, and second, you may not end up with enough statistical power to find differences between treatments. Pt.: I guess I follow you. But by not randomizing, weren’t they guaranteeing that they wouldn’t be able to compare the treatments? Dr. Carlat: They were, and I’m sure some of the researchers are regretting that decision. But it may not have been a total loss. Within each of the treatment arms, patients were randomized to a specific treatment. Thus, patients who chose to switch to another antidepressant were randomly assigned to treatment with Effexor XR (average dose 194 mg/day), Wellbutrin SR (283 mg/day), or Zoloft (135 mg/day). Pt.: So there was a randomized doubleblind component to STAR-D! Dr. Carlat: Randomized, yes, but not double blind. Patients and their doctors knew what medications they were assigned to. This is a problem, because we don’t know how much of the response to these meds was due to the actual medication vs. positive or negative expectations on the part of patients or their treaters. Pt.: I assume you’re referring to the placebo effect– that “extra” benefit that even a
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sugar pill provides if people believe in it. But could the placebo effect play a big enough role here to significantly affect the response rates? Dr. Carlat: Unfortunately, yes. In one study that looked at all antidepressant studies submitted to the FDA from 1987 to 1997, the placebo effect was shown to account for 75% of all improvement on active treatment (Khan et al, Arch Gen Psychiatry 2000;57:311-317). That’s why it’s so important for studies to incorporate a placebo control. Pt.: I understand. Still, just out of curiosity, which of the “switch to” treatments did the best? Dr. Carlat: Effexor XR did the best, with a 25% remission rate, followed by Wellbutrin SR (21%) and Zoloft (18%). But these differences were not statistically significant, and since there was no placebo comparison, we don’t know whether patients would have done just as well if they had been kept on Celexa for an extra few weeks. And while there was a “signal” that Effexor was superior, this slight advantage may have been due entirely to higher expectations, since Effexor already had a reputation in psychiatric circles as being more effective than SSRIs. Pt.: So what’s the bottom line for a patient like me? If I don’t end up responding to an SSRI, which drug should I switch to? Dr. Carlat: Unfortunately, because of the
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SSRI Nonresponse: What to do Next?
necessitating the dreaded “antidepressant gap” of at least two weeks (five weeks for Prozac). Anecdotally, some patients weather this transition better if prescribed lithium, lamotrigine, an atypical antipsychotic, or a benzodiazepine – all of which are perfectly safe when combined with MAOIs. Of course, if switching isn’t working, you should re-evaluate the diagnosis. Look for subtle signs of psychosis, bipolar disorder, substance abuse or any
other psychiatric disorder that would alter the treatment plan.
SSRI Nonresponse: No clear guidelines, but plenty of options.
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Q & A
This Month’s Expert: Michael Thase, M.D., on Deciphering Antidepressant Research
Professor of Psychiatry University of Pittsburg School of Medicine
Dr. Thase has disclosed that he has served as a consultant to AstraZeneca, Bristol-Myers Squibb Company, Cephalon, Inc., Cyberonics, Inc., Eli Lilly & Co., GlaxoSmithKline, Janssen Pharmaceutica, Neuronetics, Inc., Novartis, Organon, Inc., Sepracor, Inc., Shire US Inc., and Wyeth Pharmaceuticals, and is on the speaker’s bureau of AstraZeneca, Bristol-Myers Squibb Company, Cyberonics, Inc., Eli Lilly & Co., GlaxoSmithKline, Organon, Inc., Sanofi Aventis, and Wyeth Pharmaceuticals. Dr. Carlat has reviewed and edited the content and has determined that there is no commercial bias present.
With the Expert
Our policy on financial conflict of interest
Readers have wondered why we sometimes interview experts who have financial ties with pharmaceutical companies. TCPR accepts no money from the pharmaceutical industry, nor do we allow any of our writing staff or editorial board members to accept such money. HOWEVER, it is extremely difficult to locate national experts who do not have such ties. Furthermore, involvement with industry often leads to experiences and perspectives that are helpful in understanding crucial issues in research and treatment. Dr. Carlat conducts all expert interviews personally, and edits any content that appears unbalanced. Hopefully, this allows us to showcase the major figures in psychiatry without the injection of commercial bias. But ultimately, you, the reader, must be the judge. TCPR: I know that you published a famous meta-analysis several years ago in which you compared the remission rates of patients on venlafaxine with SSRIs and placebo. Can you remind us of what that study showed? Dr. Thase: This report, which was done in collaboration with two researchers from Wyeth, was based on the first eight randomized, double-blind, head-to-head comparisons between venlafaxine and SSRIs (Thase et al, Br J Psychiatry 2001 Mar;178:234-241). Five of the eight studies used fluoxetine, two used paroxetine and one used fluvoxamine. It didn’t include any sertraline or citalopram studies, and escitalopram wasn’t an approved medication at the time, so it wasn’t included either. That paper was heavily dependent on the studies that used fluoxetine. “In order to show TCPR: And I remember clearly that there was kind of a rule of thumb that everya difference between a good body was discussing after your study came out which was that we can expect remission rates of 45% on Effexor, 35% on SSRIs and 25% on placebo. Is that an drug and a better drug, you accurate description of your findings? need a very large number of Dr. Thase: Yes, it is an accurate summary. There is so much cynicism today about the subjects, and there are very, results of industry-sponsored research. The findings became controversial, both very few studies that are that because there’s honest room for disagreement and because the findings were marketed large. Regrettably, STAR-D is very vigorously by Wyeth and “counter-detailed” by the manufacturers of the SSRIs – not one of those studies.” Lilly, GlaxoSmithKline, Pfizer, and then later, Forest. TCPR: Looking back on the results with the perspective of time, do you think – Michael Thase, M.D. the main result is still valid – that Effexor is better at producing remission than the SSRIs? Dr. Thase: I think that it is a true finding, although the degree of venlafaxine’s advantage may have been overestimated in the original analysis, because the main SSRI comparator was fluoxetine. Recall that fluoxetine and its metabolite have very long elimination half lives, so that it takes about six weeks before it gets to steady state. Because of this, you may not see fluoxetine’s full effectiveness until you get out to at least eight or nine weeks. But even this point is still pretty controversial. It also may be true that a dual reuptake inhibitor has an advantage in some patient groups – such as older patients with more severe depression – but little if any advantage in others, such as younger women with less severe depressive episodes. TCPR: Has the venlafaxine advantage held up in more recent studies? Dr. Thase: A somewhat smaller average difference has been observed in the more recent studies, perhaps because most of those trials use lower doses of the extended release formulation of venlafaxine. So in the more recent wave of studies, the remission
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rates on venlafaxine have been more in the lower 40s on average, whereas the SSRI remission rate has remained steady at 35%. I have always felt that when you use the whole dose range of venlafaxine – up to 375mg/day – you do get a few more percent of people better. One caveat that I should mention is that there are still only two direct comparisons of venlafaxine and escitalopram and, pooling these two studies, there is no evidence of an advantage for venlafaxine. TCPR: Has the reported remission rate from SSRIs started to creep up at all from that 35% figure? Dr. Thase: Actually, that 35% remission rate on the SSRIs has held rock solid compared to about a 25% remission rate on placebo. The only studies that report higher remission rates for SSRIs have also reported higher placebo response rates. You’ll see a few studies showing a 45% remission rate on SSRIs, but they don’t emphasize that in those studies there is a 35% remission rate on placebo. TCPR: I’m not sure I understand. Why do the placebo rates increase? Is it possible to manipulate placebo rates to make your drug look better? Dr. Thase: It’s not really a matter of “manipulation.” Over the years, as the benefits of antidepressants have become increasingly well known, the proportion of people with significant depression who are willing to come into a placebo-controlled study has been shrinking and shrinking. TCPR: In other words, the people who come into antidepressant trials now are not as sick as they used to be? Dr. Thase: Yes. The placebo response rate is often an indication of how easy to treat the patient population is. There is a paper by Walsh in which they looked at the temporal trend in placebo response rates to antidepressants from 1970 to 2000, and it has been increasing slowly and steadily (Walsh et al, JAMA 2002;287(14):1840-1847). So it doesn’t surprise me to see placebo response rates in new studies of 45%, 48%, even 50%. TCPR: And how should a higher placebo response rate affect our interpretation of these studies? Dr. Thase: The real benefit is measured by how much the active drug surpasses the placebo response. Typically, a good, strong antidepressant will cause 10-20% of people to respond more than a placebo, but it will also lose about 5-10% more of the participants because of dropouts due to side effects, because placebo doesn’t have strong side effects, by and large. For example, if you take an initial 15% difference, subtract the 5% due to dropouts, then that is your standard 10% difference in an intent-to-treat analysis. Thus, if you see a 55% remission rate vs. a 45% placebo rate, this is really no better than a 35% vs. 25% placebo rate. TCPR: Meaning that the seemingly higher remission rates that we have been seeing in recent SSRI studies can’t fairly be compared with the venlafaxine remission rates from older studies, because the placebo rates were lower back then. Dr. Thase: Right. TCPR: More recently, we have seen results from the STAR-D study. I know you were one of the investigators on those trials. The results have been viewed by many as discouraging; what’s your take? Dr. Thase: STAR-D really illustrates how pernicious a condition depression is, how difficult to treat it is, and how in our optimism to help people we sometimes overestimate the likely benefits of particular treatments. In STAR-D’s case we also were somewhat surprised by the risk of relapse after successful treatment. Everybody in STAR-D got free medication and excellent follow-up care at a very low cost and for an entire year after they were successfully treated. If you think about most health service delivery systems, it doesn’t get any better than that. And in that context, about 50% of the patients had sufficient increase in symptoms over a year to have met the definition of relapse. So when you do finally bring about remission in somebody with a difficult-to-treat depression, you can’t simply relax. At the very least you need to provide psychoeducation to enhance treatment adherence. TCPR: How do STAR-D’s results fit in the context of your belief that venlafaxine has an advantage over SSRIs? Dr. Thase: When patients were switched from citalopram to venlafaxine, they had a 25% remission rate vs. an 18% remission rate on sertraline. Interestingly, the ratio of 25 to 18 is very similar to the ratio of 45 to 35, the response rates in my original meta-analysis. TCPR: But the difference wasn’t statistically significant in STAR-D. Dr. Thase: The difference wasn’t statistically significant because the treatment groups contained only about 220 patients and in order to find a difference of that size, you needed to have about 500 patients per cell. TCPR: Can you elaborate a bit on that? Dr. Thase: Most studies comparing active treatments aren’t large enough to truly resolve whether one active treatment is better than another. Studies that are calibrated to show the difference between a good drug and a placebo don’t need huge numbers, but in order to show a difference between a good drug and a better drug, you need a very large number of subjects, and there are very, very few studies that are that large. Regrettably, STAR-D is not one of those studies.
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IN PSYCHIATRY ANTIPSYCHOTICS
Conventionals: Not only cheaper than atypicals, but more effective? The latest results from the CATIE trial indicate that treatment with Trilafon (perphenazine) is not only much cheaper than treatment with SGAs (second generation antipsychotics), but leads to superior overall quality of life for patients. It’s a little confusing, because Phase One results of CATIE seemed to endorse Zyprexa as the most effective drug, as measured by “time to discontinuation.” In this study, the outcome of interest was the score on the “QALY” (quality-adjusted life year), a survey that takes into account both health gains and health losses (mainly due to side effects). Thus, while patients in CATIE may have stayed on Zyprexa longer, their overall quality of lives were better on Trilafon (Rosenheck et al, Psychiatry 2006;163:2080-2089). TCPR’s take: This is another ringing endorsement of the effectiveness of intermediate potency conventional antipsychotics, which likely incur a risk of TD somewhat higher than SGAs, but lower than high potency conventionals such as Haldol.
confusion (Schneider et al, N Engl J Med 2006;355:1525-1538). TCPR’s take: Antipsychotics are likely to quell agitation in some patients with AD, but be hyper-aware of possible side effects and have a low threshold for switching to something else. turists were blinded to the identity of the intervention. At eight weeks, response rates were as follows: specific treatment, 22%; placebo, 39%; waitlist, 17% (Allen et al, J Clin Psychiatry 2006;67(11):16651673). TCPR’s take: In the discussion section, the authors try to salvage acupuncture’s reputation by arguing that the nonspecific needling may have inadvertently been the active treatment. We don’t buy it. We all know that placebos are “active,” but the aim of the study was to show that a specific treatment has a specific therapeutic action. Studies endorsing placebo are a dime a dozen and don’t help us decide between treatments.
Suicidality and Antidepressants Another study has been published on the controversial issue of whether antidepressants increase the risk of suicidality in children. Researchers found that suicide rates among children and adolescents were lowest in U.S. counties that had higher antidepressant prescription rates (Gibbons et al, Am J Psychiatry 2006;163:1898-1904). TCPR’s Take: We’re not convinced that this finding contributes much to the debate. This was a retrospective, observational study, and the results are almost certainly confounded by the fact that counties with higher antidepressant prescribing rates have other qualities that could lead to lower suicide rates, such as generally more progressive attitudes about the treatment of mental illness. On the other hand, the original research prompting the black box warning was based on double blind randomized controlled trials, which is the best type of research in clinical science (Hammad et al, Arch Gen Psychiatry 2006;63:332-339). It is clear from that study that antidepressants can cause a mild increase in suicidal ideation in children, but not actual suicide.
It’s Official: Topamax doesn’t work
for Bipolar Disorder It’s been a bad, bad year for Topamax (topiramate). First, the results of four controlled trials of Topamax as monotherapy for mania showed that it outperforms placebo in only two ways: more paresthesia and more weight loss (Kushner et al, Bipolar Disorders 2006;8:15-27). The latest blow concerns a very common intervention in psychiatry: the addition of Topamax to lithium or Depakote as a way of augmenting their anti-manic actions. Who hasn’t tried this? Researchers randomly assigned 287 manic or mixed manic patients to either adjunctive Topamax (average dose 255 mg/day) or adjunctive placebo. After 12 weeks, there were no treatment differences in either the primary or secondary measures, though Topamax produced about 5 lbs. more weight loss than placebo (Chengappa et al, J Clin Psychiatry 2006;67(11):1698-1706). TCPR’s take: Topamax now joins Neurontin (gabapentin) in the “Looks Good in Open Trials but Bombs in Controlled Trials” club. But might Topamax still enjoy plenty of off-label use as a weight loss agent in bipolar disorder? Definitely, but don’t expect insurance companies to pay for it.
Should We Still use Atypicals for Alzheimer’s Disease? Only after thinking long and hard about it, according to the long anticipated results from the CATIE-AD trial. In this study, 421 patients with Alzheimer’s Disease were randomized to double-blind treatment with Zyprexa (mean dose, 3.2 mg/day), Seroquel (34.1 mg/day), Risperdal (0.7 mg/day), or placebo. There were no significant differences between any of the treatments in time to discontinuation. Zyprexa and Risperdal were more effective in terms of reducing behavioral symptoms than placebo (Seroquel didn’t beat placebo on this, probably because the protocol led to its underdosing) but this advantage was offset by a higher incidence of side effects on atypicals, especially sedation and
Acupuncture for depression? Not. In the largest ever randomized controlled trial of acupuncture for depression, the treatment did no better than “non-specific” needling; in fact, it did somewhat worse. A total of 151 patients with moderate depression were randomized to one of three groups: acupuncture specific to each patient’s depressive symptoms (the active group); acupuncture using a comparable number of points but without any connection to depressive symptoms (placebo); and waitlist. Both patients and acupunc-
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The Carlat Psychiatry Report CME Post-Test
To earn CME credit, you must read the articles and complete the quiz below, answering at least four of the questions correctly. Mail a photocopy or fax the completed page (no cover sheet required) to Clearview CME Institute, P.O. Box 626, Newburyport, MA 01950; fax: (978) 499-2278. For customer service, please call (978) 499-0583. Only the first entry will be considered for credit and must be received by Clearview CME Institute by December 31, 2007. Acknowledgment will be sent to you within six to eight weeks of participation. This activity has been planned and implemented in accordance with the Essential Areas and Policies of the Accreditation Council for Continuing Medical Education (ACCME) through the sponsorship of the Clearview CME Institute. Clearview CME Institute is accredited by the ACCME to provide continuing medical education for physicians. Clearview CME Institute designates this educational activity for a maximum of one (1) AMA PRA Category 1 CreditTM. Physicians should only claim credit commensurate with the extent of their participation in the activity. Please identify your answer by placing a checkmark or an “X” in the box accompanying the appropriate letter.
1. The Star-D results [ ] a. Showed that augmentation of antidepressants is an effective strategy. [ ] b. Are not clearly useful because of the lack of double-blinding or placebo. [ ] c. Are primarily relevant to mildly depressed patients. [ ] d. Are biased because of funding from the pharmaceutical industry. 2. For patients who do not respond to an SSRI, [ ] a. Increasing the dose after 8 weeks may lead to limited benefits in partial responders. [ ] b. Increasing the dose after 2 to 3 weeks increases response. [ ] c. Switching to a different SSRI is more effective than “staying the course.” [ ] d. Switching to Wellbutrin SR is generally the best option. 3. Topamax (topirimate) is effective as adjunctive treatment, but not as monotherapy, for bipolar mania. [ ] a. True [ ] b. False 4. According to the CATIE-AD trial, [ ] a. Atypical antipsychotics caused higher mortality than placebo in patients with Alzheimer’s Disease (AD). [ ] b. Atypicals were not effective for agitation but improved cognition in AD. [ ] c. Atypicals were no better than placebo on the primary outcome measure (time to discontinuation). [ ] d. Atypicals caused a surprisingly high incidence of tardive dyskinesia. 5. According to Dr. Thase, Effexor’s apparent efficacy advantage over SSRIs has stood the test of time. [ ] a. True [ ] b. False
PLEASE NOTE: WE CAN AWARD CME CREDIT ONLY TO SUBSCRIBERS PLEASE NOTE: WE CAN AWARD CME CREDIT ONLY TO SUBSCRIBERS First Name Street Address City Phone State Fax Zip E-mail Last Name Degree (MD, DO, NP etc.) ,
Your evaluation of this CME activity (i.e., this issue) will help guide future planning. Please respond to the following questions: 1. Did the content of this activity meet the stated learning objectives? [ ] Yes [ ] No 2. On a scale of 1 to 5, with 5 being the highest, how do you rank the overall quality of this educational activity? [ ] 5 [ ] 4 [ ] 3 [ ] 2 [ ] 1 3. As a result of meeting the learning objectives of this educational activity, will you be changing your practice behavior in a manner that improves your patient care? Please explain. [ ] Yes [ ] No 4. Did you perceive any evidence of bias for or against any commercial products? Please explain. [ ] Yes [ ] No 5. How long did it take you to complete this CME activity? ___ hour(s) ___ minutes 6. Important for our planning: Please state one or two topics that you would like to see addressed in future issues.
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How Do STAR-D Results Help our Depressed Patients?
way STAR-D was designed, it provides us no help at all in answering that question. Pt.: That’s frustrating. But what about the augmentation arm? Dr. Carlat: Patients who decided to stay on their Celexa were randomly assigned to augmentation with either BuSpar (average dose, 41 mg/day) or Wellbutrin SR (267 mg/day). Pt: Let me guess: this was open label, and there was no placebo group? Dr. Carlat: It was open-label, but in this case, the researchers inadvertently included a kind of placebo treatment: BuSpar. In all three prior placebo-controlled trials of BuSpar augmentation of SSRIs, BuSpar has never done better than placebo (J Clin Psychiatry. 1998 Dec;59(12):664-8; J Clin Psychiatry. 2001 Jun;62(6):448-52; J Affect Disord. 2003 Sep;76(1-3):223-7). So in essence, BuSpar acted as a placebo control for Wellbutrin augmentation. Pt.: And how did Wellbutrin augmentation do? Dr. Carlat: No better than BuSpar/placebo. They both produced 30% remission rates. Nonetheless, we can’t really interpret this as implying that Wellbutrin is ineffective for augmentation, because, like the rest of STAR-D, this arm was not double-blinded. High or low expectations may have significantly altered remission rates on either treatment, in an unpredictable way. This means that these augmentation results, like the switch results, provide no guidance to clinicians. Pt.: But what about the rest of the study? Dr. Carlat: Patients who did not come to remission in any step could go into additional trials. But again, all of these minitrials were open label, and none included a placebo group, so none of the data resulting from them is of any clear use to clinicians. Here are the numbers: For Step 3: Switch to Remeron (12.3% remission rate) vs. switch to Nortriptyline (19.8%); Lithium augmentation (16%) vs. thyroid augmentation (25%). And for Step 4: Switch to Parnate (7%) vs. switch to Effexor + Remeron (14%). Pt.: I can see that you’re not very impressed with the STAR-D results. But the latest press release from the American Psychiatric Association was much more positive. To quote it: “Results indicate that 67 percent of patients who complete from one to four treatment steps can reach remission.” Dr. Carlat: Yes, the idea that there was a 67% “cumulative remission rate” was
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reported in the most recent paper on STAR-D, which was a summary analysis of the entire trial (Rush et al, Am J Psychiatry 2006;163:1905-1917). This was an example of creative statistics. For example, in prior papers, the primary outcome measure was reported as the industry – standard Hamilton Depression Scale (HamD), whereas this analysis used only the QIDS-SR16 (self report), which consistently yielded higher remission rates than the Hamilton. Furthermore, this analysis restores 795 patients who had originally been deemed ineligible because their depression was too mild (HamD scores < 14). By doing this, they enriched the sample with patients who were already very close to remission, thereby inflating apparent remission rates. Pt.: So where does this leave us? Dr. Carlat: Pretty much where we were before STAR-D: Start with an SSRI, hope it works, and then move on to whatever strategy we prefer, based on our clinical experience and our understanding of the literature.
STAR-D’s biggest lesson: How not to spend our next $35 million!
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This Month’s Focus: Antidepressant Round-up 2007
Next Month in The Carlat Psychiatry Report: Understanding Psychiatric Research, including a primer on how to critically read journal articles, what “statitiscal significance” really means, and some clarity on “relative risk,” “odds ratios,” and “number needed to treat.”
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